Chronic rhinosinusitis with polyps (CRSwNP) is a significant health problem in the United States. This disorder, which is often particularly recalcitrant to medical and surgical therapy, is characterized by persistent eosinophilic inflammation of the sinonasal mucosa, with thickened secretions that are frequently colonized with micro-organisms. The cellular and molecular mechanisms that underlie CRSwNP remain poorly understood. The epithelium of nose and sinuses participates actively in host immunity, serving as a barrier and first line of defense against inhaled pathogens and other potential threats. In previous studies, we investigated how sinonasal epithelial cells (SNEC) contribute to CRSwNP through production of innate pro-eosinophilic mediators and by bidirectional communication with other immune cells. Our research using human tissue and mouse models have suggested that SNEC are triggered by epithelial damage to produce mediators that promote eosinophilic inflammation. We hypothesize that this pathway, involving innate lymphoid cells (ILCs), is a normal aspect of healing and repair. Our latest findings suggest that the populations of ILCs and epithelial basal progenitor cells differ in CRSwNP. To test the hypotheses regarding basal cell and ILC interaction, we will initially, in aim 1, examine sinus mucosa from patients with chronic sinus inflammatory disease to define subtypes of basal progenitor cells and explore their innate immune function and pro-eosinophilic mediator expression. We will also employ novel cell culture models to understand the properties of basal cell populations. In aim 2, we will explore type 2 ILCs in CRSwNP and their interaction with basal cell populations, using cell culture models. Finally, in aim 3, we will investigate the innate immune activity of polyp basal cells in a modified cell culture model, and we will utilize genetically-modified mice and nasal inflammation models to explore the role of innate immune regulation of basal cells in healing and persistence of eosinophilic inflammation after injury. These studies will significantly advance current knowledge about CRSwNP and create an opportunity to develop innovative therapies for this debilitating and costly medical condition.